Mounting evidence suggests that some autistic children may be susceptible to an environmental pathogen (most likely a virus or bacterium) resulting from an inherited deficiency of their immune system. Unable to clear the pathogen in a timely and normal fashion, the child would be at increased risk for the pathogen (or pathogenic toxins) to directly interfere with developing brain (or brain function) and/or lead to the generation of an autoimmune mechanism that interferes with brain functioning. Circumstantial evidence for this hypothesis stems from the number of features that autism shares with established immune and autoimmune disorders including: genetic predisposition; general immune imbalances; association with viral and other infections; demonstration of antibodies in the serum against proteins of the central nervous system and an uneven sex distribution. We have recently found additional evidence for the pathogen-autoimmune hypothesis for some cases of autism including an increased frequency of the C4B null allele and elevated representations of the extended haplotype B44-S30-DR4 and two DRbeta1 HVR-3 alleles. All of these genes are part of the major histocompatibility complex that exerts important control over immune function. This component focuses on several recently observed preliminary abnormalities that we have observed in autism which may be related to the WA genes. Findings obtained in this component also will be correlated with results obtained in the other components of this grant including stratification of autism by psychiatric, cognitive, neuroimaging and electroretinographic parameters. Specifically, this component will: perform HLA studies and determine C4 plasma levels on additional autistic and normal subjects; attempt to establish a possible relationship between the HLA system and elevated serotonin levels in autism; explore the basis of possible MHC- associated immunoglobulin IgA deficiency in some autistic subjects; attempt to confirm and expand studies on WA-restricted reactivity with cells of the autistic child by the maternal immune system.